1. Field of the Invention
The present invention relates to a series of substituted tetracyclic heteroaromatic benzofuranoindoles and indenoindoles having pharmacological activity, to a process for their preparation, to pharmaceutical compositions containing them, and to their use in the treatment of disorders associated with smooth muscle contraction, via potassium channel modulation. Such disorders include, but are not limited to: urinary incontinence, asthma, premature labor, irritable bowel syndrome, congestive heart failure, angina, and cerebral vascular disease.
2. Description of the Prior Art
Modulation of potassium channels remains at the forefront of current approaches for controlling resting cell membrane potential and affecting cell excitability. A wide variety of discrete potassium channels exist and these have been thoroughly classified according to structure, function, pharmacological properties, and gating mechanisms in several recent reviews [Rudy, B. Neuroscience 1988, 25, 729-749; Atwal, K., Medicinal Research Reviews 1992, 12, 569-591; Gopalakrishnan, M. et al., Drug Development Research 1993, 28, 95-127; Primeau, J. et al. Current Pharmaceutical Design 1995, 1, 391-406; Edwards, G. et al. Exp. Opin. Invest. Drugs 1996, 5 (11), 1453-1464]. Activation of these channels augments transmembrane K.sup.+ flux, thus effecting hyperpolarization of the cell membrane towards the Nernst K.sup.+ equilibrium potential (-90 mV), and subsequent closure of the voltage-gated Ca.sup.2+ channels. As a result, the hyperactive cell becomes less excitable and therefore less prone to further stimulation; thus leading to relaxation in the case of smooth muscle. As a result of this pharmacologic action, therapeutic potential for potassium channel activators in cardiovascular disorders, metabolic disorders, central nervous system disorders, bronchial asthma, and irritable bladder is being vastly explored.
A series of heterotetracyclic methylamnino benzofuranoindoles compounds are reported by Bair, K. W., in WO 91/14688 and EP-447703-A1 and are useful as antitumor and biocidal agents. ##STR2##
An example disclosed is 2-methyl-2-(((10-methyl- 10H-benzofuro(3,2-b)indol-6-yl)methyl)amino)-1,3-propanediol.
A series of indenoindoles claimed as useful medicinal antioxidants and free-radical scavengers are disclosed by Sainsbury et al. in EP-404536-A1. ##STR3##
A series of indenoindoles useful as a component in an organic electroluminescent element are disclosed in JP-06-228554. ##STR4##
X is --O--, --S, -, SO.sub.2 -, or --NR.sup.9 PA1 R.sub.1, R.sub.2 and R.sub.3 are, independently, hydrogen, halogen, nitro, cyano, alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms (optionally substituted with halogen), amino, alkylamino of 1 to 10 carbon atoms, --SO.sub.3 H, --SO.sub.2 NH.sub.2, --NHSO.sub.2 R.sub.14, ##STR7## PA1 Y is --O-- and-NR.sub.4 ; PA1 X is --O--, when Y is --NR.sub.4 ; PA1 X is --NR.sub.4, when Y is --O--; PA1 R.sub.4 is hydrogen, alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, aryl of 6 to 12 carbon atoms, or an acyl substituent selected from formyl, alkanoyl of 2 to 7 carbon atoms, alkenoyl of 3 to 7 carbon atoms, alkylsulfonyl of 1 to 7 carbon atoms, aroyl of 7 to 12 carbon atoms, arylalkenoyl of 9 to 20 carbon atoms, arylsulfonyl of 6 to 12 carbon atoms, arylalkanoyl of 8 to 12 carbon atoms and arylalkylsulfonyl of 7 to 12 carbon atoms; PA1 R.sub.5 and R.sub.6 are independently hydrogen, alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, aryl of 6 to 12 carbon atoms, or fluorine; PA1 a) Y is --NR.sub.4 when X is --O--; PA1 Z is --CO.sub.2 H; PA1 R.sub.1 is halogen or nitro; PA1 R.sub.1, R.sub.2 and R.sub.3 are, independently, hydrogen, halogen, nitro, cyano, alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms (optionally substituted with halogen), amino, alkylamino of 1 to 10 carbon atoms, --SO.sub.3 H, --SO.sub.2 NH.sub.2, --NHSO.sub.2 R.sub.14, ##STR10## PA1 Y is --NR.sub.4 and --CR.sub.5 R.sub.6 ; PA1 X is --O--, when Y is --NR.sub.4 ; PA1 X is --NR.sub.4, when Y is --CR.sub.5 R.sub.6 ; PA1 X is --CR.sub.5 R.sub.6, when Y is --NR.sub.4 ; PA1 R.sub.4 is hydrogen, alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, aryl of 6 to 12 carbon atoms, or an acyl substituent selected from formyl, alkanoyl of 2 to 7 carbon atoms, alkenoyl of 3 to 7 carbon atoms, alkylsulfonyl of 1 to 7 carbon atoms, aroyl of 7 to 12 carbon atoms, arylalkenoyl of 9 to 20 carbon atoms, arylsulfonyl of 6 to 12 carbon atoms, arylalkanoyl of 8 to 12 carbon atoms and arylalkylsulfonyl of 7 to 12 carbon atoms; PA1 R.sub.5 and R.sub.6 are independently hydrogen, alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, aryl of 6 to 12 carbon atoms, or fluorine; PA1 a) X is --O--, when Y is --NR.sub.4 ; PA1 b) X is --NR.sub.4, when Y is --CR.sub.5 R.sub.6 ; and PA1 c) X is --CR.sub.5 R.sub.6, when Y is --NR.sub.4. PA1 Z is --CO.sub.2 H; PA1 R.sub.1 is halogen or nitro;
A related series of tetrahydro indeno-indole analogs is disclosed by Sainsbury, M. in WO 90/15799 and in EP-409410-B1. ##STR5##
These compounds are also claimed as useful antioxidants for the treatment of atherosclerosis, thrombosis, embolism and Parkinson's disease.
The synthesis and antioxidant properties of a series of indeno-indoles and indolines are reported in several papers [Brown, D. W. et al., Tetrahedron 1991, 47 (25), 4383-4408; Brown, D. W. et al., Tetrahedron 1993, 49 (39), 8919-8932; Graupner, P. R. et al., Tetrahedron Lett. 1995, 36 (32) 5827-5830; Shertzer, H. G. et al., Fd. Chem. Tox. 1991, 29 (6) 391-400]. Reported also by Brown, F. C. et al., Tetrahedron Lett. 1991, 32 (6) 801-802 are flash-vacuum pyrolysis methods for the synthesis of substituted indeno[1,2-b]indoles.
The present invention differs from the prior art by requiring the Z substituent, defined below as a carboxylic acid moiety, a bioisosteric equivalent of a carboxylic acid, or a derivative thereof to be substituted at position a of the tetracyclic heteroaromatic benzofuranoindoles and indenoindoles of Formulae (I) and (II). The compounds of this invention have reported potassium channel activation and the resulting smooth muscle relaxing properties are uniquely tissue-selective for bladder tissue.